Attila Nakeeb, M.D. completed his residency training in General Surgery at the Johns Hopkins Hospital (1991-1999) and spent two years as a research fellow (1993-1995) in the laboratory of Dr. Henry A. Pitt investigating biliary malignancies and gallstone pathogenesis. He is currently an Assistant Professor of Surgery at the Medical College of Wisconsin (MCW) and continues to have a strong interest in biliary diseases. Dr. Nakeeb is seeking this Mentored Patient-Oriented Research Career Development Award (K-23) to study the genetic loci influencing human gallbladder disease. The long-term goal of this research focus is to understand the role of genetic pathogenic mechanisms underlying gallbladder dysfunction, which in turn can lead to new strategies to prevent gallstone formation. A career development plan consisting of didactic coursework, participation in national seminars and institutional research meetings, close and frequent interaction with mentors, and completion of the research plan is proposed to allow the mastering of competencies and research skills necessary to become a successful clinical investigator. The environment at MCW is ideally suited to study the genetics of human gallbladder disease. A cohort of 2209 individuals from 509 nuclear families has undergone basic phenotyping for obesity as well as DNA genotyping. A subset of these families are participating in refined obesity phenotyping at MCW, and are available for the determination of gallbladder disease specific phenotypes. The specific aims of this proposal are as follows: 1) To characterize potential endophenotypes related to the risk of developing gallbladder disease including presence of gallstones, size and number of stones, gallbladder wall thickness, and gallbladder response to a fat meal 2) To conduct univariate and multivariate quantitative genetic analyses on the phenotypes of gallbladder disease, and 3) To analyze a genome wide scan to identify quantitative trait loci with measurable effects on the expression of gallbladder disease risk factors. The completion of this research plan and the training and knowledge acquired from the mentors should allow Dr. Nakeeb to develop into an independent clinical scientist.